One of the hallmarks of AD pathology is the presence of neuritic plaques in the brains of afflicted individuals. These plaques are composed of extracellular deposits of amyloid beta peptide (Ab) surrounded by dystrophic neurites, reactive astrocytes, and microglia. The interaction of copper with Ab enhances Ab aggregation and induces the production of Ab-Cu-mediated free radical formation and oxidative stress. It is hypothesized that Ab-mediated toxicity is potentiated by extracellular copper, and increases in the concentration of copper and the copper transport protein ceruloplasmin are found in the CSF of AD patients. This proposal is based on our recent observations that the immunophilin FKBP52 is a novel component of the copper efflux pathway in mammalian cells and down-modulation of FKBP52 expression with siRNA or small molecule inhibitors block copper efflux from the Atox1-Wilson's disease protein (WDP) copper export pathway. The basic question therefore is presented; Can FKBP52 be exploited as a therapeutic target for controlling copper levels and AD progression? This proposal will test the hypothesis that siRNA or small molecule drugs that target the immunophilin will ameliorate the development and evolution of Ab pathology in both cellular models and in a mouse APPswe/PS1dE9 model for amyloidosis. This proposal seeks to address three specific questions. [unreadable] [unreadable] Aim #1. To characterize APP processing, Ab production, and to quantify intracellular copper in cells treated with immunophilin ligands (FK506 or JNJ460) or in FKBP52-downmodulated cells. [unreadable] [unreadable] Aim #2. To determine whether Ab-induced oxidative damage and neurotoxicity is alleviated in FKBP52 down-modulated neuron-glia co-cultures. [unreadable] [unreadable] Aim #3. To investigate if Ab deposition and Ab-mediated synaptic pathology is affected by FKBP52 down-modulation using an inducible mouse model under the control of the tet-off system, and in animals chronically treated with immunophilin ligands (FK506 and JNJ460). [unreadable] [unreadable] [unreadable]